Ocular analyte sensor

ABSTRACT

An ophthalmic lens comprising a receptor moiety can be used to determine the amount of an analyte in an ocular fluid. The receptor moiety can bind either a specific analyte or a detectably labeled competitor moiety. The amount of detectably labeled competitor moiety which is displaced from the receptor moiety by the analyte is measured and provides a means of determining analyte concentration in an ocular fluid, such as tears, aqueous humor, or interstitial fluid. The concentration of the analyte in the ocular fluid, in turn, indicates the concentration of the analyte in a fluid or tissue sample of the body, such as blood or intracellular fluid.

This application is a continuation in part of PCT application PCT/EP00/0825 filed Aug. 24, 2000, now pending, which claims the benefits ofU.S. provisional application No. 60/150,792 filed Aug. 26, 1999 and U.S.provisional application No. 60/185,980 filed Mar. 1, 2000.

BACKGROUND OF THE INVENTION

An ophthalmic lens comprising a receptor moiety can be used to determinethe amount of an analyte in an ocular fluid which is accessible tolight. The receptor moiety can bind either a specific analyte or adetectably labeled competitor moiety. The amount of detectably labeledcompetitor moiety which is displaced from the receptor moiety by theanalyte is measured and provides a means of determining analyteconcentration in an ocular fluid, such as tears, aqueous humor, orinterstitial fluid. The concentration of the analyte in the ocularfluid, in turn, indicates the concentration of the analyte in a fluid ortissue sample of the body that is not as accessible, such as blood orintracellular fluid.

Various noninvasive or minimally invasive methods to measure analytes,particularly glucose, have been described. For example, March, U.S. Pat.Nos. 3,958,560 and 4,014,321, discloses a glucose sensor wherein apatient's eye is automatically scanned using a source of light at oneside of the cornea. A sensor located at the other side of the corneadetects the light that passes through the cornea. The level of glucosewhich rotates the plan of polarized light in the aqueous humor of thepatient is a function of the amount of radiation detected. However, thissensor system is not necessarily specific or widely applicable todetection of analytes other than glucose, because it does not exploitthe use of biological molecules which can detect glucose or otheranalytes in a body tissue or fluid sample. Biological molecules, as iswell known, can provide very specific and sensitive detection reagentsfor particular analytes.

Schultz, U.S. Pat. No. 4,344,438, discloses a system for monitoring lowmolecular weight compounds in blood plasma by optical means, whichinvolves a chamber which contains specific receptor sites for the plasmaconstituent to be analyzed. This system is very invasive, however,because it must be implanted within the blood stream using a hypodermicneedle. The system also inherently contains the risks of clotting aroundthe device, obstruction, and other adverse reactions, including immunereactions, general irritation, and foreign body reactions.

BRIEF SUMMAARY OF THE INVENTION

Embodiments of the present invention overcome these disadvantages in theprior art by employing an ophthalmic lens comprising a receptor moietywhich comprises an analyte/competitor moiety binding site to detect ananalyte in an ocular fluid. Concentration of a wide variety of analytescan be measured using an ophthalmic lens according to embodiments of theinvention. Such analytes include, but are not limited to, electrolytesand small molecules (e.g., sodium, potassium, chloride, phenylalanine,uric acid, galactose, glucose, cysteine, homocysteine, calcium, ethanol,acetylcholine and acetylcholine analogs, ornithine, blood urea nitrogen,creatinine), metallic elements (e.g., iron, copper, magnesium),polypeptide hormones (e.g., thyroid stimulating hormone, growth hormone,insulin, luteinizing hormones, chorionogonadotrophic hormone),chronically administered medications (e.g., dilantin, phenobarbital,propranolol), acutely administered medications (e.g., cocaine, heroin,ketamine), small molecule hormones (e.g., thyroid hormones, ACTH,estrogen, cortisol, estrogen, and other metabolic steroids), markers ofinflammation and/or allergy (e.g., histamine, IgE, cytokines), lipids(e.g., cholesterol), plasma proteins and enzymes (e.g., complement,coagulation factors, liver function enzymes, heart damage enzymes,ferritin), markers of infection (e.g., virus components, immunoglobulinssuch as IgM, IgG, etc., proteases, protease inhibitors), and/ormetabolites (e.g., lactate, ketone bodies).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates an analyte sensor system including acontact lens of the invention according to a preferred embodiment of theinvention.

FIG. 2A and FIG. 2B schematically show an analyte sensor systemincluding an intraocular lens of the invention according to a preferredembodiment of the invention.

FIG. 2C is schematic flow chart of signal transmission in an analytesensor system of the invention according to a preferred embodiment.

FIG. 3A schematically illustrates a contact lens of the invention as ananalyte sensor.

FIG. 3B schematically illustrates a subconjunctival lens of theinvention as an analyte sensor.

FIG. 3C schematically illustrates an intra-corneal lens of the inventionas an analyte sensor.

FIG. 4 shows the relationship between fluorescence intensity of anfluorescent intraocular lens of the invention at three glucoseconcentrations in vitro.

FIG. 5 schematically shows effects of fluorescein concentrations on thesensitivity of glucose detection using the rhodamine-concanavalinAlfluorescein-dextran in a sensor.

Ophthalmic lenses according to embodiments of the invention can be usedto monitor the course of therapy or the level of disease in mammals,including primates and, preferably, humans. In addition, becauseophthalmic lenses according to embodiments of the invention provide away to detect analytes noninvasively, they provide distinct advantagesover more traditional forms of monitoring such levels. Ophthalmic lensesaccording to embodiments of the invention also are useful for diagnosticpurposes, for example to test for pregnancy (to detect β-HCG), to assessblood chemistry (electrolytes, Ca₂PO₄, magnesium, bilirubin, alkalinephosphatase, lactate dehydrogenase, alanine aminotransferase, etc.), andto detect infection (e.g., by detecting components of viruses such asCMV, EBV, hepatitis, and HIV, or bacteria, such as Staphlococcus,Streptococcus, etc.). They also are useful for monitoring blood levelsof test compounds during the course of assessing the compounds for useas potential therapeutics.

Ophthalmic lenses according to embodiments of the invention can be wornchronically to provide repeated analyte measurements or can be worn fora single analyte measurement. Both qualitative and quantitativemeasurements can be performed.

Ophthalmic Lens

An ophthalmic lens according to embodiments of the invention can be aremovable lens, such as a contact lens, or a permanently implanted lens,such as an intraocular lens, a subconjunctival lens, or an intracorneallens. See U.S. Ser. Nos. 60/150,792 and 60/185,980, the patentapplications the priority of which is claimed for this invention.Permanently implanted lenses are particularly well-suited for use inindividuals who have compromised ocular function (e.g., cataracts) andalso have chronic conditions which require analyte measurement, such asdiabetics.

Ophthalmic lenses can be corrective lenses or can be constructed so thatthey do not affect visual acuity. Contact lenses optionally can comprisea tint and are preferably disposable, which reduces the risk ofinfection for the user. As used herein, the term “ophthalmic lens” mayalso refer to a shunt or implant that may rest in the cul de sac of theeye.

Receptor Moiety

The ophthalmic lens comprises a receptor moiety. The receptor moietycomprises a binding site for the analyte to be detected. The bindingsite also binds a moiety which competes with the analyte for binding andis therefore referred to herein as an “analyte/competitor moiety bindingsite.” Binding of both the competitor moiety and the analyte to theanalyte/competitor moiety binding site is reversible. The nature of themolecule used as the receptor moiety depends on the particular analyteto be detected, but minimally includes that portion of the moleculewhich is sufficient to contain an analyte/competitor moiety bindingsite.

For example, if glucose is the analyte to be detected, the receptormoiety preferably is concanavalin A (Mansouri & Schultz, Bio/Tech 2,385, 1984), although other moieties, such as antibodies, boronic acid, agenetically engineered bacterial fluoriprotein, or glucose oxidase alsocan be used.

Boronic acid derivatives may also be used as competitive moieties forglucose, as they form covalent complexes with glucose. For example, acombination of a fluorescence moiety, such as anthracene, boronic acidand tertiary amine gives a sensor for glucose. Illustrative, but nonelimiting boronic acid compounds are listed below:

Glucose binds with the acidic boronic moiety creating a fluorescentmoiety.

If phenylalanine is the analyte to be detected, the receptor moietypreferably comprises the active site of phenylalanine hydroxylase. It iswell within the skill of those knowledgeable in the art to determineother analyte-receptor moiety binding pairs, such as uric acid-uricase,alcohol-alcohol dehydrogenase, copper-ceruloplasmin,galactose-galactokinase, cysteine- and/or homocysteine-cystathioninesynthetase, acetylcholine-acetylcholinesterase, ornithine-diamineoxidase, and the like.

Competitor Moiety

For use in detecting an analyte, an ophthalmic lens according toembodiments of the invention preferably comprises a competitor moietyhaving a detectable label. The competitor moiety competes with theanalyte for binding to the analyte/competitor moiety binding site. Thedetectable label can intrinsically be part of the competitor moiety.Alternatively, the detectable label can be a label which is notnaturally associated with the competitor moiety but which is attached bymeans of a chemical linkage, such as a covalent bond. In preferredembodiments, the competitor moiety comprises a fluorescent label. Otherdetectable labels, such as luminescent or calorimetric labels, also canbe used.

Again, it is well within the skill of those in the art to select acompetitor moiety which will compete with an analyte for binding to aparticular analyte/competitor moiety binding site. For example,competitor moieties which can be used with the analyte-receptor moietybinding pairs disclosed above include fluorescein dextran (whichcompetes with glucose for binding to concanavalin A), fluoresceinpolyglutamylurate (which competes with uric acid for binding touricase), fluorescein nanolol (which competes with alcohol for bindingto alcohol dehydrogenase), fluorescein-glutamine phenylacetate (whichcompetes with phenylalnine for binding to phenylalanine hydroxylase),fluorescein-erythrocuprein (which competes with copper for binding toceruloplasmin), fluorescein-2,3,6-tri-O-methyl galactose (which competeswith galactose for binding to galactokinase), fluorescein-S-adenosylpolyhomocysteine (which competes with cysteine and homocysteine forbinding to cystathionine synthetase), fluoropolyglutamyl prostigmine(which competes with acetylcholine for binding to acetylcholinesterase),and fluorospermine (which competes with ornithine for binding to diamineoxidase).

Most preferably, the detectable label is more readily detectable whenthe competitor moiety is not bound to the analyte/competitor moietybinding site. Thus, fluorescent labels, such as fluorescein, indocyaninegreen, malachite green, and rhodamine, which are quenched when thecompetitor moiety is bound but are unquenched when the competitor moietyis not bound, are preferred for use in ophthalmic lenses according toembodiments of the invention.

In addition, the sensitivity of the monitor can be controlled byaltering the concentration of the detectable label. For example, thefree resonance energy transfer function, an indicator of measurementsensitivity, can be increased by increasing the concentration of thedetectable label. Thus in the case of fluorescein dextran (whichcompetes with glucose for binding to concanavalin A), increasing theconcentration of fluorescein on the competitive moiety increases therange of fluorescence intensity. Increasing the range of fluorescenceintensity increases the sensitivity of resulting measurements.

The principle is illustrated in FIG. 5. Two different fluoresceindextran compounds, each with differing fluorescein concentrations, weretested in the same glucose environments and the fluorescence intensitymeasured. Sigma FITC-Dextran has a fluorescein concentration of 2% andM.P. Fluorescein-Dextran has a fluorescein concentration of 4%. Eachsolution was measured in a fluorophotometer with variable wavelength.The first peak is characteristic of fluorescein, the second ofrhodamine. As can be seen from FIG. 5, M.P. Fluorescein-Dextran, thecompound with the higher fluorescein concentration has a greater rangeof fluorescence intensity as measured at a given wavelength than theSigma FITC-Dextran. The larger range of fluorescence gives greatersensitivity when measuring patient glucose levels.

It is important to note the purity of the competitive moiety caninfluence the activity level of the detectable label. For example, inthe case of fluorescein dextran, the relative level of monomers, dimersor tetramers can influence the sensitivity. Relatively pure levels ofdimers seem to positively influence sensitivity.

Providing Receptor and Competitor Moieties in an Ophthalmic Lens

A variety of options are available for providing the receptor andcompetitor moieties in an ophthalmic lens. Construction of various typesof ophthalmic lenses is well known in the art. Construction of contactlenses is taught, for example, in U.S. Pat. Nos. 5,965,631, 5,894,002,5,849,811, 5,807,944, 5,776,381, 5,426,158, 4,099,859, 4,229,273,4,168,112, 4,217,038, 4,409,258, 4,388,164, 4,332,922, 4,143,949,4,311,573, 4,589,964, and 3,925,178.

Construction of intraocular lens implants is taught, inter alla, in U.S.Pat. Nos. 6,051,025, 5,868,697, 5,762,836, 5,609,640, 5,071,432,5,041,133, and 5,007,928. Subconjunctival lenses are taught, forexample, in U.S. Pat. Nos. 5,476,511, 5,400,114, and 5,127,901.Intracorneal lenses are taught, inter alia, in U.S. Pat. Nos. 6,090,141,5,984,961, 5,123,921, and 4,799,931.

In one embodiment, the receptor moiety is covalently bound to theophthalmic lens material. In another embodiment, the ophthalmic lenscomprises a polymer meshwork containing pores. The pores are of a sizewhich permit the competitor moiety to bind reversibly to theanalyte/competitor moiety binding site, but which prevent the receptormoiety and the competitor moiety from diffusing out of the ophthalmiclens. Suitable polymers for this purpose are known in the art andinclude hydrogels, such as stable polymers of polyethylene glycolhydrogel (PEGH) (March et al., 2000), and modified polyvinylalcohol,such as nelfilcon A.

In another embodiment, the ophthalmic lens comprises a receptor moietylayer, a polyelectrolyte layer, and a competitor moiety layer. Thepolyelectrolyte layer includes one or more polyelectrolytes, which aregenerally high molecular weight polymers with multiple ionic orionizable functional groups. At least one polyelectrolyte in thepolyelectrolyte layer has a charge opposite to the overall charge of thereceptor moiety and competitor moiety layers. Suitable polyelectrolytesinclude positively charged PDDA (polydiallyidimethylammonium chloride)and negatively charged PAA (polyacrylic acid). Assembly of the layers isbased upon sequential adsorption of oppositely charged polyions. Thesensor and spacing polyelectrolytes are deposited as uniform thin films(1-10 nm) in 10-15 deposition cycles onto the porous polyvinyl alcoholor hydrogen matrix, resulting in only a 100-500 nm thick coating for thesensing film, which is highly biocompatible. A typical sequence forconstruction of an ophthalmic lens suitable for glucose detectioninvolves a deposition cycle of ultrathin (1-10 nm) films of PDDA, PM,PDDA, concanavalin A, PDDA, PAA, PDDA, fluorescein dextran, PDDA, PM,PDDA, PM, concanavalin A, PAA, fluorescein dextran, PM, etc. Technologyfor constructing ophthalmic lenses comprising such layers is taught, forexample, in WO 99/35520.

An ophthalmic lens according to embodiments of the invention can beprovided in a kit, together with instructions for measuring analyteconcentration as described below. The invention provides kits which areintended for individual patient use, in which the ophthalmic lenstypically is a contact lens, as well as kits for medical practitioners,which can comprise any of the ophthalmic lenses or their equivalentsdescribed herein.

Analyte Sensor System

An ophthalmic lens according to embodiments of the invention can be usedin an analyte sensor system. The analyte sensor system comprises anophthalmic lens and a detector configured to detect the detectablelabel. For example, if the label is a luminescent label, the detectormay include a luminometer; if the label is a colorimetric label, thedetector may include a colorimeter; if the label is a fluorescent label,the detector may include a fluorophotometer. Construction of suchdevices is well known in the art. Light with wavelengths which willexcite the fluorescent label can be provided, for example, by a laser ora light source, such as a light-emitting diode. A fluorophotometersuitable for use with embodiments of the invention can be constructedusing a light-emitting diode from Power Technology, Inc. (Little Rock,Ark.) (see March et al., Diabetes Technol. & Ther. 2, 27-30, 2000).

The detector can be a free-standing device, a table-top device, or ahand-held device. For convenience, the detector can be a miniaturizeddevice and may be worn or carried as a personal accessory, for example,mounted in the frame of a pair of eyeglasses, clipped to an article ofclothing, such as a shirt or sweater, hung around the neck, worn aroundthe wrist, or clipped to a belt or a key ring.

Using an ophthalmic lens in an analyte sensor system, as describedabove, embodiments of the invention provides methods of measuringanalyte concentration in an ocular fluid. This measurement can, in turn,be manipulated to provide a measurement of the analyte's concentrationin a body tissue or a fluid, such as blood or intracellular fluid. Therelationship between glucose concentration in the aqueous humor and theblood, for example, is well known. See Süllmann, in HANDBUCH DERPHYSIOLOGISCHEN CHEMIE, Vol. II/a, p. 867 ff., Springer, Berlin, 1956;Graymore, in THE EYE, Vol. I, p. 348, Davson, ed., Academic Press, NY,1962; De Berardinis et al, Exp. Eye Res. 4, 179, 1965; Pohjola, ActaOphthalmologica Suppl. 88, 1966; Reim et al., Ophthalmologica 154,39-50, 1967; Kinsey & Reddy, in Prince, ed., THE RABBIT AND EYERESEARCH, C. C. Thomas, Springfield, Ill., 1964, p. 218. Therelationship between the concentration of another analyte in a bodytissue or fluid and the concentration of the analyte in an ocular fluidcan be determined by methods well known in the art. See, for example,March et al, Diabetes Care 5, 259-65, 1982. The detector can beconfigured to convert the measurement of the analyte concentration intoa value which reflects the concentration of the analyte in the relevantbody tissue or fluid, e.g., blood.

If desired, the analyte sensor system also can comprise a transmitterconfigured to transmit a signal representing whether the detectablelabel is detected and/or an amount of the detectable label that isdetected. A device configured to vary the concentration of the analytein a body fluid or tissue, such as an infusion pump or other pump, mayreceive the signal and may vary the concentration response to thesignal. The signal from the analyte sensor system may comprise acontinuous or discontinuous telemetry signal generated by the detector.The pump may, in response to the signal, adjust the levels of theanalyte in the body by providing the user with the appropriate amount ofa regulator moiety, such as insulin. Infusion pumps are well known inthe art for delivering a selected medication to a patient includinghumans and other animals in accordance with an administration schedulewhich can be preselected or, in some instances, preprogrammed. Pumps foruse in this invention can be worn externally or can be directlyimplanted into the body of a mammal, including a human, to deliver aspecific medication such as insulin to the mammal in controlled dosesover an extended period of time. Such pumps are well known and aredescribed, for example, in U.S. Pat. Nos. 5,957,890, 4,923,375,4,573,994, and 3,731,681. Medications which should optimally bemaintained at a constant level, such as phenobarbital, baclofen,theophylline, and cardiac and blood pressure medications, also can beprovided by means of an infusion pump.

Illustrative Embodiments

Illustrative embodiments of the analyte sensor system according toembodiments of the invention are shown in FIGS. 1 and 2. FIG. 1 is aschematic view of an analyte sensor system employing a contact lens 1, aradiation detector 5, such as a fluorophotometer, and a radiation source2, such as a laser (which preferably is of low power) or light emittingdiode, which emits light 3 with a first wavelength which will excite thefluorescent label in competitor moieties contained within the contactlens 1. In response to the light 3, competitor moieties which are notbound to receptor moieties will thereby emit light 4 of a seconddifferent wavelength (e.g., by fluorescence), which can be detected andmeasured by a radiation detector 5. The radiation detector 5 and theradiation source 2 may be embodied together as a hand-held unit, asshown in FIG. 1.

Conveniently, a miniaturized version of the radiation source 2 and theradiation detector 5 can be configured to be built into a pair ofeyeglasses. An exemplary embodiment of this is shown in FIGS. 2A and 2B.The analyte sensor system shown in FIGS. 2A and 2B employs anintraocular lens 8, which comprises a polymer 9 containing receptormoieties and fluorescently labeled competitor moieties. A light-emittingdiode 6 is mounted in the frame of a pair of eyeglasses 7. Thelight-emitting diode 6 emits light 3 with a first wavelength which willexcite the fluorescent label in the competitor moieties. Competitormoieties which are not bound to receptor moieties will thereby emitlight 4 of a second different wavelength, which can be detected andmeasured by a fluorophotometer 5, which is mounted together with thelight-emitting diode 6 in the eyeglasses frame 7. A telemetry signal 10is transmitted to an infusion pump 11, which can provide a regulatormoiety, such as insulin, to maintain suitable levels of the analyte inthe body The telemetry signal 10 may be analog or digital and may betransmitted via wire or cable, such as wire 60, or wirelessly, such asvia radio frequency or infrared transmission. Where the telemetry signal10 is transmitted wirelessly, the analyte sensor system may includeantennas 50, 51, for such wireless transmission. Antenna 50 may, ifdesired, be embedded within eyeglass frame 7. As shown in FIG. 2C, theantennas 50, 51 may be coupled with a respective wireless transmitter 52and wireless receiver 53.

The telemetry signal 10 may include qualitative information as towhether or not the analyte is detected by the radiation detector 5. Forexample, where the detected light 4 is at or exceeds a predeterminedthreshold, the telemetry signal 10 may represent a “detected” state(such as the existence of telemetry signal 10). Where the detected light4 is below the threshold, the telemetry signal 10 may represent a “notdetected” state (such as the absence of telemetry signal 10).Alternatively, the telemetry signal 10 may indicate a change in analyteconcentration. Telemetry signal 10 also may provide a warning signal ifthe analyte concentration is above or below a preset range.

Optionally, the telemetry signal 10 may include quantitative informationas to how much light 4 is detected by the radiation detector 5. Forinstance, the telemetry signal 10 may be varied in amplitude and/orfrequency responsive to the amount of light 4 detected, where theamplitude and/or frequency represents the amount of light 4. As anotherexample, the telemetry signal 10 may include digital data representingthe amount of detected light 4.

If the telemetry signal 10 is analog, the telemetry signal 10 may begenerated by the detector 5, which may include a modulator forgeneration of the telemetry signal 10. If the telemetry signal 10 isdigital, the telemetry signal 10 may be generated by ananalog-to-digital (“A/D”) converter 70. Also, the amount of the light 4detected by the radiation detector 5 may be shown on a display 71 (whichmay include a display driver), such as a CRT screen or liquid crystaldisplay (“LCD”).

All patents and patent applications cited in this disclosure areexpressly incorporated herein by reference. The above disclosuregenerally describes the present invention. A more complete understandingcan be obtained by reference to the following specific examples whichare provided for purposes of illustration only and are not intended tolimit the scope of the invention.

EXAMPLE 1

Construction of an Intraocular Glucose Sensor

A structurally stable polymer of polyethylene glycol hydrogel (PEGH,Shearwater Polymers, Inc.) is used to construct an intraocular glucosesensor. PEGH is immobilized in an intraocular lens (Alcon Laboratories,6 mm circumference, 1 mm thickness). Chemically immobilized pendanttetramethylrhodamine isothiocyanate concanavalin A (TRITC-ConA, Sigma)is incorporated into the PEGH as the receptor moiety and fluoresceinisothiocyanate dextran (FITC-dextran, Sigma) is incorporated as thecompetitor moiety by polymerization under UV light, as described byBallerstadt & Schultz, Anal. Chim. Acta 345, 203-12, 1997, and Russell &Pishko, Anal. Chem. 71, 3126-32, 1999. While the FITC-dextran is boundto the TRITC-ConA, the FITC fluorescence is quenched via a fluorescenceresonance energy transfer. Increased glucose concentration frees theFITC-dextran and results in fluorescence which is proportional toglucose concentration.

FIG. 4 shows the relationship between fluorescence intensity of ourfluorescent intraocular lens at three glucose concentrations in vitro. Alinearly proportional relationship occurs between 0 and 500 mg % at 518nm, which is the peak of fluorescein fluorescence. The peak at 575 nm isdue to the rhodamine in the TRITC-ConA.

EXAMPLE 2

Implantation of an Intraocular Glucose Sensor In Vivo

The intraocular lens glucose sensor described in Example 1 is implantedinto the anterior chamber of the eye of a living New Zealand rabbit witha blood glucose concentration of 112 mg %. The implant is visible as abright spot of green fluorescence (518 nm) within the eye. Carefulexamination with a biomicroscope slit lamp shows no sign of toxicity,rejection, or any reaction 6 months after implantation.

What is claimed is:
 1. An apparatus for detecting an analyte in anocular fluid, comprising: an ophthalmic lens; a receptor moiety inand/or on said ophthalmic lens, wherein said receptor moiety comprisesan analyte/competitor moiety binding site, wherein the analyte canreversibly bind at said analyte/competitor moiety binding site; and adetectable label in and/or on said ophthalmic lens.
 2. The apparatus ofclaim 1 which further comprises a competitor moiety comprising thedetectable label in and/or on the ophthalmic lens.
 3. The apparatus ofclaim 1 which is selected from the group consisting of a contact lens,an intraocular lens, a subconjunctival lens, an intracorneal lens, and ashunt or implant that can rest in the cul de sac of an eye.
 4. Theapparatus of claim 1, wherein the analyte is selected from the groupconsisting of an electrolyte, a metallic element, a polypeptide hormone,a chronically administered medication, an acutely administeredmedication, a small molecule hormone, a marker of inflammation, a markerof allergy, a lipid, a protein, a marker of infection, and a metabolite.5. The apparatus of claim 1, wherein the ocular fluid is selected fromthe group consisting of tears, aqueous humor, and interstitial fluid. 6.The apparatus of claim 1, wherein said ophthalmic lens comprises saidreceptor moiety therein, wherein the receptor moiety is covalently boundto lens material of the ophthalmic lens.
 7. The apparatus of claim 2,wherein said ophthalmic lens comprises said receptor moiety therein,wherein said ophthalmic lens comprises a polymer meshwork, wherein poresof the polymer meshwork (a) permit the competitor moiety to bindreversibly to the analyte/competitor moiety binding site and (b) preventthe receptor moiety and the competitor moiety from diffusing out of theophthalmic lens.
 8. The apparatus of claim 2, wherein said ophthalmiclens comprises a coating on the surface of said ophthalmic lens, whereinthe coating includes: a receptor moiety layer; a polyelectrolyte layer;and a competitor moiety layer.
 9. The apparatus of claim 2, wherein thedetectable label is a fluorescent label.
 10. An apparatus for detectingglucose in an ocular fluid, comprising an ophthalmic lens having acoating thereon, wherein the coating includes: a receptor moiety layer,wherein receptor moieties in the receptor moiety layer compriseglucose/competitor moiety binding sites; a first and a secondpolyelectrolyte layer; and a competitor moiety layer, wherein competitormoieties in the competitor moiety layer comprise detectable labels. 11.The apparatus of claim 10, wherein the receptor moiety layer comprisesconcanavalin A molecules.
 12. The apparatus of claim 10, wherein thecompetitor moiety layer comprises fluorescein dextran molecules.
 13. Ananalyte sensor system, comprising: (a) an ophthalmic lens for detectingan analyte in an ocular fluid, comprising: (i) a receptor moiety whichcomprises an analyte/competitor moiety binding site; and (ii) acompetitor moiety comprising a detectable label; and (b) a detectorconfigured to detect the detectable label.
 14. The analyte sensor systemof claim 13, wherein the detector includes a fluorophotometer.
 15. Theanalyte sensor system of claim 13, further comprising a transmittercoupled to the detector and configured to transmit to a pump a signalindicating whether the detectable label is detected by the detector,wherein the pump is configured to vary a concentration of the analyte ina body fluid or tissue.
 16. The analyte sensor system of claim 15,wherein the transmitter is contained in a personal accessory.
 17. Theanalyte sensor system of claim 15, further comprising the pump.
 18. Theanalyte sensor system of claim 15, wherein the transmitter is furtherconfigured to transmit the signal to the pump wirelessly.
 19. Theanalyte sensor system of claim 15, wherein the analyte is glucose andthe body fluid is blood.
 20. The analyte sensor system of claim 19,wherein the receptor moiety is concanavalin A.
 21. The analyte sensorsystem of claim 19, wherein the competitor moiety is fluoresceindextran.
 22. The analyte sensor system of claim 19, wherein the pump isan insulin pump.
 23. The analyte sensor system of claim 13 wherein theophthalmic lens is selected from the group consisting of a contact lens,an intraocular lens, a subconjunctival lens, an intracorneal lens, randa shunt or implant that can rest in the cul de sac of an eye.
 24. Theanalyte sensor system of claim 13, wherein the ophthalmic lens comprisesa polymer meshwork, wherein pores of the polymer meshwork (a) permit acompetitor moiety to bind reversibly to the analyte/competitor moietybinding site and (b) prevent the receptor moiety and the competitormoiety from diffusing out of the ophthalmic lens.
 25. The analyte sensorsystem of claim 13, wherein the ophthalmic lens comprises a coating onits surface, wherein the coating includes: a receptor moiety layerincluding the receptor moiety; a polyelectrolyte layer; and a competitormoiety layer including the competitor moiety.
 26. The analyte sensorsystem of claim 13, wherein the ocular fluid is selected from the groupconsisting of tears, aqueous humor, and interstitial fluid.
 27. A methodfor measuring the concentration of an analyte in an ocular fluid,comprising the steps of: (a) contacting the ocular fluid with anophthalmic lens, wherein the ophthalmic lens comprises: (i) a receptormoiety which comprises an analyte/competitor moiety binding site; and(ii) a competitor moiety which comprises a detectable label; and (b)detecting the detectable label, wherein the amount of detectable labeldetected indicates the concentration of the analyte in the ocular fluid.28. The method of claim 27, wherein the ophthalmic lens is selected fromthe group consisting of a contact lens, an intraocular lens, asubconjunctival lens, an intracorneal lens, and a shunt or implant thatcan rest in the cul de sac of an eye.
 29. The method of claim 27,wherein the analyte is selected from the group consisting ofelectrolytes and small molecules, metallic elements, polypeptidehormones, chronically administered medications, acutely administeredmedications, small molecule hormones, markers of inflammation, markersof allergy, lipids, proteins, markers of infection, and metabolites. 30.The method of claim 27, wherein the ocular fluid is selected from thegroup consisting of tears, aqueous humor, and interstitial fluid. 31.The method of claim 27, wherein the receptor moiety is covalently boundto lens material of the ophthalmic lens.
 32. The method of claim 27,wherein the ophthalmic lens comprises a polymer meshwork, wherein poresin the polymer meshwork (a) permit a competitor moiety to bindreversibly to the analyte/competitor moiety binding site and (b) preventthe receptor moiety and the competitor moiety from diffusing out of theophthalmic lens.
 33. The method of claim 32, wherein the ocular fluid isselected from the group consisting of tears, aqueous humor, andinterstitial fluid.
 34. The method of claim 27, wherein the ophthalmiclens comprises a coating on its surface, wherein the coating includes: areceptor moiety layer including the receptor moiety; a polyelectrolytelayer; and a competitor moiety layer including the competitor moiety.35. The method of claim 27, wherein the detectable label is afluorescent label.
 36. A method for varying the concentration of ananalyte in an ocular fluid, comprising the steps of: (a) contacting theocular fluid with an ophthalmic lens, wherein the ophthalmic lenscomprises: (i) a competitor moiety which comprises a detectable label;and (ii) a receptor moiety which comprises an analyte/competitor moietybinding site; (b) detecting the detectable label, wherein the amount ofdetectable label detected indicates the concentration of the analyte ina body tissue or fluid; (c) transmitting a signal indicating theconcentration of the analyte in the ocular fluid to a pump configured tovary the concentration of the analyte in the body tissue or fluid; and(d) providing a regulator moiety via the pump to the body tissue orfluid, whereby the concentration of the analyte in the body tissue orfluid is varied.
 37. The method of claim 36 wherein the detectable labelis a fluorescent label.
 38. The method of claim 37 wherein thedetectable label is detected by a fluorophotometer.
 39. The method ofclaim 38 wherein the fluorophotometer is contained in a personalaccessory.
 40. The method of claim 36 wherein the ocular fluid isselected from the group consisting of tears, aqueous humor, andinterstitial fluid.
 41. The method of claim 36 wherein the analyte isglucose.
 42. The method of claim 41 wherein the receptor moiety isconcanavalin A.
 43. The method of claim 41 wherein the competitor moietyis fluorescein dextran.
 44. The method of claim 41 wherein the regulatormoiety is insulin.
 45. The method of claim 36 wherein the ophthalmiclens is selected from the group consisting of a contact lens, anintraocular lens, a subconjunctival lens, an intracorneal lens, and ashunt or implant that can rest in the cul de sac of an eye.
 46. Themethod of claim 36, wherein the receptor moiety is covalently bound tolens material of the ophthalmic lens.
 47. The method of claim 36,wherein the ophthalmic lens comprises a polymer meshwork, wherein poresof the polymer meshwork (a) permit a competitor moiety to bindreversibly to the analyte/competitor moiety binding site and (b) preventthe receptor moiety and the competitor moiety from diffusing out of theophthalmic lens.
 48. The method of claim 36, wherein the ophthalmic lenscomprises on its surface a coating including: a receptor moiety layerhaving the receptor moiety; a polyelectrolyte layer; and a competitormoiety layer having the competitor moiety.
 49. A kit for detecting ananalyte in an ocular fluid, comprising: an ophthalmic lens comprising areceptor moiety which comprises an analyte/competitor moiety bindingsite; and instructions for using the ophthalmic lens to detect theanalyte.
 50. The kit of claim 49, further comprising a competitor moietycomprising a detectable label.
 51. The kit of claim 50, furthercomprising a detector configured to detect the detectable label.
 52. Akit for detecting glucose in an ocular fluid, comprising: a contact lenscomprising concanavalin A and fluorescein dextran; and instructions forusing the contact lens to detect glucose in the ocular fluid.
 53. Thekit of claim 52, further comprising a detector for detectingfluorescence of fluorescein dextran which is not bound to theconcanavalin A.